rs187200982

chr13-51942395-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000053.4(ATP7B):c.3403G>A(p.Ala1135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,614,070 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1135A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (94 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.97

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021026433).
• BP6: Variant 13-51942395-C-T is Benign according to our data. Variant chr13-51942395-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51942395-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3403G>A	p.Ala1135Thr	missense_variant	15/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3403G>A	p.Ala1135Thr	missense_variant	15/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 152142 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00603 AC: 1504 AN: 249374 Hom.: 43 AF XY: 0.00579 AC XY: 783 AN XY: 135328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00643

GnomAD4 exome AF: 0.00251 AC: 3675 AN: 1461810 Hom.: 94 Cov.: 32 AF XY: 0.00248 AC XY: 1807 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0548

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00466 AC: 710 AN: 152260 Hom.: 19 Cov.: 32 AF XY: 0.00674 AC XY: 502 AN XY: 74438

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000808 Hom.: 2

Bravo AF: 0.000329

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.00518 AC: 626

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATP7B: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.0050
Dann	Benign	0.53
DEOGEN2	Uncertain	0.52	D;T;.;.;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.45	T;T;T;T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.14	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.19	N;N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.60	T;T;T;T;T;.;T
Sift4G	Benign	0.60	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B
Vest4		0.12
MVP		0.65
MPC		0.058
ClinPred		0.013	T
GERP RS		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs187200982; hg19: chr13-52516531;